This Program Project Hormonal Control of Calcium Metabolism brings together a group of highly productive investigators who work closely together, as they have for years, supported by the project and stimulated by the environment of the Endocrine Unit. Powerful research tools feature the approaches of chemical and molecular biology and a number of carefully designed genetically modified animals to evaluate bone and renal cell biology as well as mineral metabolism. Exciting medical translational applications have already been initiated from this work. Project I, Mechanisms of action of PTH ligands on the PTHR1 and implications in vivo (Gardella PI), has led to the development of a new therapy for hypoparathyroidism (in collaboration with NIGH BrIDGs program), exciting new directions in peptide design including signal selective compounds and newer types of long-acting PTH molecules, as well as peptidomimetics (in collaboration with NlH's small molecule screening program MLPCN). Project II, PTH actions on cells of the osteoblast lineage (Kronenberg PI), and Project III, Role of PTH/PTHrP receptor and RANKL in osteoblastic cells in vivo (Divieti Pajevic PI), are independent but closely related projects that explore the cellular responses in bone to PTH employing powerful new techniques developed by the investigators to study the proliferation and differentiation of cells of the osteoblast lineage in vivo, roles of histone deacetylases in the cellular responses to bone anabolic actions of PTH and results of deletion of the PTH receptor in osteoblastic cells at varying stages of differentiation. This effort is fundamental to understanding how to improve the therapeutic response to PTH in fracture healing and in patients with osteoporosis. Project IV, PTH actions on renal target cells in the regulation of renal phosphate excretion (Jueppner PI), examines key features of signal selectivity in PTH action, especially on renal phosphate transport and the desensitization of the cAMP/PKA pathway with chronic PTH exposure with the ensuing compensation by the IP3/PKC pathway, emphasizing the potential role of PTH ligands with enhanced IP3/PKC signaling in improving treatment in chronic renal disease (CKD).